Arylsulfonamide derivatives as c-jun-n-terminal kinases (jnk&#39;s) inhibitors

ABSTRACT

The present invention relates to sulfonamide derivatives of formula I notably for use as pharmaceutically active compounds, as well as to pharmaceutical formulations containing such sulfonamide derivatives. Said sulfonamide derivatives are useful in the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases. Furthermore, said sulfonamide derivatives are efficient modulators of the JNK pathway, they are in particular efficient and selective inhibitors of JNK2 and -3. The present invention is furthermore related to novel sulfonamide derivatives as well as to methods of their preparation. 
     
       
         
         
             
             
         
       
         
         
           
             Ar 1  is a substituted or unsubstituted aryl or heteroaryl group; 
             X is O or S, preferably O; 
             Ar 2  a substituted or unsubstituted arylene or heteroarylene group; 
             R 1  and R 2  are independently selected from the group consisting of hydrogen and a C 1 -C 6 -alkyl group;

FIELD OF THE INVENTION

The present invention is related to novel sulfonamide derivatives aswell as to methods of their preparation. The present invention isfurther related to sulfonamide derivatives for use as pharmaceuticallyactive compounds, as well as pharmaceutical formulations containing suchsulfonamide derivatives. In particular, the present invention is relatedto sulfonamide derivatives useful in the treatment and/or prevention ofapoptosis related disorders and inflammatory diseases. Furthermore, thepresent invention is related to sulfonamide derivatives displaying asubstantial modulatory, notably an inhibitory, activity of thec-Jun-N-Terminal Kinases (JNKs) function or pathways respectively.

BACKGROUND OF THE INVENTION

Mammalian cells respond to some extracellular stimuli by activatingsignaling cascades which are mediated by various mitogen-activatedprotein kinases (MAPKs). Despite the differences in their response toupstream stimuli, the MAP kinase cascades are organized in a similarfashion, consisting of MAP kinase kinase kinases (MAPKKK or MEKK), MAPkinase kinases (MAPKK or MKK) and MAP kinases (MAPK). MAP kinases are abroad family of kinases which includes c-Jun N-Terminal kinases (JNKs),also known as “stress-activated protein kinases” (SAPKs), as well asextracellular signal regulated kinases (ERKs) and p38 MAP kinases. Eachof these three MAP kinases sub-families is involved in at least threedifferent but parallel pathways conveying the information triggered byexternal stimuli. The JNK signaling pathway is activated by exposure ofcells to environmental stress—such as chemical toxins, radiation,hypoxia and osmotic shock—as well as by treatment of cells with growthfactors or pro-inflammatory cytokines—such as tumour necrosis factoralpha (TNF-α) or interleukin-1 beta (IL-1β).

Two MAP kinase kinases (known as MKKs or MAPKKs), i.e. MKK4 (known alsoas JNKK1) and MKK7, activate JNK by a dual phosphorylation of specificthreonine and tyrosine residues located within a Thr-Pro-Tyr motif onthe activation loop on the enzyme, in response to cytokines and stresssignals. Even further upstream in the signaling cascade, MKK4 is knownto be activated itself also by a MAP kinase kinase kinase, MEKK1 throughphosphorylation at serine and threonine residues.

Once activated, JNK binds to the N-terminal region of transcriptionfactor targets and phosphorylates the transcriptional activation domainsresulting in the up-regulation of expression of various gene products,which can lead to apoptosis, inflammatory responses or oncogenicprocesses (1-5).

Some transcription factors known to be JNK substrates are the Junproteins (c-jun, JunB and JunD), the related transcription factors ATF2and ATFa, Ets transcription factors such as Elk-1 and Sap-1, the tumorsuppressor p53 and a cell death domain protein (DENN):

Three distinct JNK enzymes have been identified as products of the genesJNK1, JNK2 and JNK3 and ten different isoforms of JNK have beenidentified (3, 6, 7). JNK1 and -2 are ubiquitously expressed in humantissues, whereas JNK3 is selectively expressed in the brain, heart andtestes (7, 8, 9, 10). Each isoform binds to the substrates withdifferent affinities, suggesting, in vivo, a substrate specificregulation of the signaling pathways by the different JNK isoforms.

Activation of the JNK pathway has been documented in a number of diseaseprocesses, thus providing a rationale for targeting this pathway fordrug discovery. In addition, molecular genetic approaches have validatedthe pathogenic role of this pathway in several diseases.

For example, auto-immune and inflammatory diseases derive from theinappropriate activation of the immune system. Activated immune cellsexpress many genes encoding inflammatory molecules, including cytokines,growth factors, cell surface receptors, cell adhesion molecules anddegradative enzymes. Many of these genes are known to be regulated bythe JNK pathway, through the activation of the transcription factorsc-Jun and ATF-2.

The inhibition of JNK activation in bacteriallipopolysaccharide-stimulated macrophages, effectively modulates theproduction of the key pro-inflammatory cytokine, TNF-α (11).

The inhibition of JNK activation decreases the transcription factoractivation responsible of the inducible expression of matrixmetalloproteinases (MMPs) (12), which are known to be responsible of thepromotion of cartilage and bone erosion in rheumatoid arthritis and ofgeneralized tissue destruction in other auto-immune diseases.

The JNK cascade is also activated in T cells by antigen stimulation andCD28 receptor co-stimulation (13) and regulates the production of theIL-2 promoter (14). Inappropriate activation of T lymphocytes initiatesand perpetuates many auto-immune diseases, including asthma,inflammatory bowel syndrome and multiple sclerosis.

In neurons vulnerable to damage from Alzheimer's disease and in CA1neurons of patients with acute hypoxia (15), JNK3 protein is highlyexpressed. The JNK3 gene was also found to be expressed in the damagedregions of the brains of Alzheimer's patients (16). In addition, neuronsfrom JNK3 KO mice were found to become resistant to kainic acid inducedneuronal apoptosis compared to neurons from wild-type mice (8).

Based on these findings, the JNK signaling pathway and especially thatof JNK2 and JNK3, is thought to be implicated in apoptosis-drivenneurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, epilepsy and seizures, Huntington's disease, traumatic braininjuries as well as ischemic and hemorrhaging strokes.

Cardiovascular diseases, such as atherosclerosis and restenosis resultfrom defective regulation of growth of the blood vessel wall. The JNKpathway is activated by atherogenic stimuli and regulates local cytokineand growth factor production in vascular cells (17, 18) inducingpro-atherosclerotic gene (19).

Ischemia alone or coupled with reperfusion in the heart, liver, kidneyor brain results in cell death and scar formation, which can ultimatelylead to congestive heart failure, hepatic disorders, renal failure orcerebral dysfunction. The JNK pathway is activated by ischemia andreperfusion in the heart (20), leading to the activation ofJNK-responsive genes and leukcocyte-mediated tissue damage. JNKactivation is also observed in kidney (21) or liver (22) followingischemia and reperfusion. The down-regulation of JNKs has been proven toimprove renal function and long-term outcome during nephritic andischemic renal failure (23).

Cancer is characterized by uncontrolled growth, proliferation andmigration of cells. In early lung cancer, expression of c-jun is alteredand may mediate growth factor signaling in non-small cell lung cancer(24). In addition to regulating c-jun production and activity, JNKactivation can regulate phosphorylation of p53, and thus can modulatecell cycle progression (25). Moreover, the role of JNK activation inHTLV-1 (human T cell leukemia virus type 1) mediated tumorgenesis (26)suggests the potential use of JNK inhibitors in cancer treatment (27).Selective inhibition of JNK activation by a naturally occurring JNKinhibitory protein, called JNK-interacting-protein-1 (JIP1), blockscellular transformation (28). Thus, JNK inhibitors may blocktransformation and tumor cell growth.

Several small molecules have been proposed as modulators of JNK pathway.Aryl-oxindole derivatives of respectively the generic formula (A) (WO00/35909; WO 00/35906; WO 00/35921) and formula (B) (WO 00/64872) havebeen developed for the treatment of neurodegenerative diseases,inflammation and solid tumors for formula (A) and for the treatment of abroad range of disorders including, neurodegenerative diseases,inflammatory and autoimmune diseases, cardiovascular and bone disordersfor formula (B).

Pyrazoloanthrones derivatives of formula (C) have been reported toinhibit JNK for the treatment of neurological degenerative diseases,inflammatory and auto-immune disorders as well as cardiovascularpathologies (WO 01/12609).

Tetrahydro-pyrimidine derivatives of formula (D) were reported to be JNKinhibitors useful in the treatment of a wide range of diseases includingneurodegenerative diseases, inflammatory and auto-immune disorders,cardiac and destructive bone pathologies (WO 00/75118).

Other heterocyclic compounds of formula (E) have been proposed toinhibit protein kinases and especially c-Jun-N-Terminal kinases (WO01/12621) for treating “JNK-mediated conditions” includingneurodegenerative diseases, inflammatory and auto-immune disorders,destructive bone disorders, cardiovascular and infectious diseases.

Benzazoles derivatives such as represented by formula (F) (WO 01/47920)have been described as modulators of the JNK pathway and especially asselective inhibitors of JNK2 and/or JNK3 for the treatment of neuronaldisorders, auto-immune diseases, cancers and cardiovascular diseases.

Several sulphonamide derivatives of formula (G) (WO 01/23378), sulfonylamino acid derivatives of formula (H) (WO 01/23379) and sulfonylhydrazide derivatives of formula (J) (WO 01/23382), were also developedto inhibit JNKs especially JNK2 and JNK3 for treating neurodegenerativediseases, auto-iminune disorders, cancers and cardiovascular diseases.

The high relevance of the JNK pathway in some widely spread diseasesstresses the need to develop inhibitors, preferentially selective, ofJNKs, including JNK3 inhibitors.

SUMMARY OF THE INVENTION

It is an objective of the present invention to provide molecules whichare suitable for the treatment of a variety of diseases, in particularof neuronal or the autoimmune system related disorders, cancer, ischemicconditions and cardiovascular diseases.

It is notably an objective of the present invention to provide chemicalcompounds which are able to modulate, preferably to down-regulate or toinhibit the JNK (Jun kinase) pathway so to be useful in method oftreating diseases which involve the JNK pathway.

Moreover, it is an objective of the present invention to provide methodsfor preparing said chemical compounds. It is furthermore an objective ofthe present invention to provide a new category of pharmaceuticalformulations for the treatment of diseases, in particular those mediatedby the JNK function.

It is finally an objective of the present invention to provide a methodfor the treatment and/or prevention of diseases that are caused bydisorders of the autoimmune and/or the neuronal system.

In a first aspect, the invention provides compounds of formula I:

Wherein:

-   -   Ar¹ is selected from substituted or unsubstituted aryl or        heteroaryl groups;    -   Ar² is selected from substituted or unsubstituted arylene or        heteroarylene groups;    -   X is O or S, preferably O;    -   R¹ and R² are independently selected from the group consisting        of hydrogen and C₁-C₆-alkyl group;    -   R^(a), R^(a′), R^(b), R^(b′) are independently selected from the        group consisting of hydrogen and C₁-C₆-alkyl; or alternatively        R^(a′) and R^(a) or R^(b′) form, together with the carbon atoms        to which they are linked, a substituted or unsubstituted        5-8-membered saturated, partially unsaturated or aromatic ring        containing optionally one or more heteroatoms selected from O,        N, S;    -   R³ is selected from the group consisting of H, C₁-C₁₀-alkyl,        C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl or heteroaryl, 3-8 membered        cycloalkyl optionally containing 1-3 heteroatoms selected from        N, O, S, aryl C₁-C₁₀-alkyl and heteroarylC₁-C₁₀-alkyl;    -   or R³ and R^(a) or R^(a′) form, together with the N atom linked        to R³ a 5-8-membered saturated ring containing optionally at        least one further heteroatom selected from O, N, S;    -   R⁴ is selected from the group consisting of H and —C(H)R⁵R⁶;    -   R⁵ and R⁶ are independently selected from the group consisting        of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl or        heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3        heteroatoms selected from N, O, S, aryl C₁-C₁₀-alkyl and        heteroarylC₁-C₁₀-alkyl;    -   m is an integer from 1 to 5, preferably between 1-3 and most        preferably 1;    -   n is an integer from 0 to 2, preferably 0 or 1; and    -   p is an integer from 1 to 10, preferably 1 to 6; with the        proviso that the compound according to formula I is not:        Benzamide,        N-[[5-[[[3-[[4-[(3-aminopropyl)amino]butyl]amino]propyl]amino]sulfonyl]-2-thienyl]methyl]-;        nor        Benzamide,        N-[[5-[[[3-[[4-[(3-aminopropyl)amino]butyl]amino]propyl]amino]sulfonyl]-2-thienyl]methyl]-4-chloro];        nor        Benzamide,        N,N′-[1,4-butanediylbis(imino-3,1-propanediyliminosulfonyl-5,2-thiophenediylmethylene)]bis[4-chloro].

In a second aspect, the invention provides a compound according toformula I without proviso for the treatment of disease.

In a third aspect, the invention provides a compound of formula I,without proviso, for the preparation of a pharmaceutical composition.

In a fourth aspect, the invention provides a compound according toformula I without proviso for the modulation of the JNK pathway.

In a fifth aspect, the invention provides a method of synthesis of acompound according to formula I with proviso.

DETAILED DESCRIPTION OF THE INVENTION

The following paragraphs provide definitions of various chemicalmoieties and terms, and are intended to apply uniformly throughout thespecification and claims unless an otherwise expressly set outdefinition provides a different definition.

“C₁-C₆-alkyl” refers to monovalent branched or unbranched alkyl groupshaving 1 to 6 carbon atoms. This term is exemplified by groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-hexyl and the like.

“C₃-C₆-cycloalkyl” refers to saturated or partially unsaturatedcarbocyclic rings having 3 to 6 carbon atoms. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and thelike.

“C₃-C₆-heterocycloalkyl” refers to saturated or partially unsaturatedrings having 3 to 6 atoms and containing at least one heterotom selectedfrom N, S and O. Examples include pyrrolidinyl, piperidinyl,piperazinyl, imidazolidinyl, morpholinyl and the like.

“Aryl” refers to unsaturated aromatic carbocyclic groups of from 6 to 14carbon atoms having a single ring (e.g. phenyl) or multiple condensedrings (e.g. naphthyl). Examples include phenyl, naphthyl, phenanthrenyland the like.

“Aryl C₁-C₆-alkyl” refers to C₁-C₆-alkyl groups, as defined above,having an aryl substituent, including benzyl, phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl.

“Heteroaryl C₁-C₆-alkyl” refers to C₁-C₆-alkyl groups having aheteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl,2-(1H-indol-3-yl)ethyl and the like.

“C₂-C₆ Alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Examples include ethenyl (—CH═CH₂), n-2-propenyl (allyl, —CH₂CH_═CH₂)and the like.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 6 carbonatoms and having at least 1-2 sites of alkynyl unsaturation. Examplesinclude ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Acyl” refers to a group —C(O)R where R includes “C₁-C₆-alkyl”, “aryl”,“heteroaryl”, “aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.

“Acyloxy” refers to a group —OC(O)R where R includes “C₁-C₆-alkyl”,“aryl”, “heteroaryl”, “aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.

“Alkoxy” refers to a group —O—R where R includes “C₁-C₆-alkyl” or “aryl”or “hetero-aryl” or “aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.Preferred alkoxy groups include by way of example, methoxy, ethoxy,phenoxy and the like.

“Alkoxycarbonyl” refers to a group C(O)OR where R includes H,“C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “aryl C₁-C₆-alkyl” or“heteroaryl C₁-C₆-alkyl”.

“Aminocarbonyl” refers to a group —C(O)NRR′ where each R, R′ isindependently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.

“Acylamino” refers to a group —NR(CO)R′ where each R, R′ isindependently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyl” refers to a group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁-C₆-alkyl”, “C₁-C₆-alkyl” which may besubstituted with halogens e.g. an —SO₂—CF₃ group, “aryl C₁-C₆-alkyl” or“heteroaryl C₁-C₆-alkyl”.

“Sulfoxy” refers to a group “—S(O)—R” wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” which may be substituted with halogens e.g.an —SO—CF₃ group, “aryl”, “heteroaryl”, “aryl C₁-C₆-alkyl” or“heteroaryl C₁-C₆-alkyl”.

“Thioalkoxy” refers to groups —R where R includes “C₁-C₆-alkyl” or“aryl” or “heteroaryl” or “aryl C₁-C₆-alkyl” or “heteroarylC₁-C₆-alkyl”. Examples include thiomethoxy, thioethoxy, and the like.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “Alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁-C₆-alkyl”, “aryl C₁-C₆-alkyl”, “heteroarylC₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, primary, secondary ortertiary amino groups or quarternary ammonium moieties, “acyl”,“acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycarbonyl”, “aryl”,“heteroaryl”, carboxyl, cyano, halogen, hydroxy, mercapto, nitro,sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like.Alternatively said substitution could also comprise situations whereneighboring substituents have undergone ring closure, notably whenviccinal functional substituents are involved, thus forming e.g.lactams, lactons, cyclic anhydrides, but also acetals, thioacetals,animals formed by ring closure for instance in an effort to obtain aprotective group.

“Pharmaceutically acceptable salts or “complexes” refers to salts orcomplexes of the below-identified compounds of formula I that retain thedesired biological activity. Examples of such salts include, but are notrestricted to acid addition salts formed with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid,naphthalene disulfonic acid, and polygalacturonic acid. Said compoundscan also be administered as pharmaceutically acceptable quaternary saltsknown by a person skilled in the art, which specifically include thequartemary ammonium salts of the formula —NR,R′,R″⁺Z⁻, wherein R, R′, R″is independently hydrogen, alkyl, or benzyl, and Z is a counterion,including chloride, bromide, iodide, alkoxyde, toluenesulfonate,methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate,succinate, acetate, glycolate, maleate, malate, fumarate, citrate,tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained by asynthesis comprising an enantioselective step, whereby a surplus of oneenantiomer in the order of at least about 52% ee is yielded. In theabsence of an enantiomeric synthesis, racemic products are usuallyobtained that do however also have the inventive set out activity asJNKs inhibitors.

The present invention also includes the geometrical isomers, the opticalactive forms, enantiomers, diastereomers of compounds according toformula I mixtures of these, as well as their racemates and alsopharmaceutically acceptable salts.

Preferred Ar¹ and Ar² in compounds according to formula I are those thatare independently selected from the group consisting of phenyl, thienyl,furanyl, pyridyl, optionally substituted by substituted or unsubstitutedC₁-C₆-alkyl, preferably trihalomethyl, substituted or unsubstitutedC₁-C₆-alkoxy, substituted or unsubstituted C₂-C₆-alkenyl, substituted orunsubstituted C₂-C₆-alknyl, amino, acylamino, aminocarbonyl,C₁-C₆-alkoxycarbonyl, aryl, carboxyl, cyano, halo, hydroxy, nitro,sulfonyl, sulfoxy, acyloxy and C₁-C₆-thioalkoxy. Most preferably, Ar¹ isa substituted phenyl, e.g. a halogenophenyl, hydroxyphenyl, alkoxyphenyl and most preferably Ar² is an unsubstituted or substitutedthienyl or phenyl group.

A particularly preferred embodiment of the present invention is asulfonamide derivative according to formula I, wherein Ar¹ ishalogenophenyl, hydroxyphenyl, alkoxy phenyl, X is O, R¹ is hydrogen, mis 1, n is 0 or 1, p is 1 or 2, Ar² is thienylene or phenylene group,preferably a thienylene group and R^(a), R^(a′), R^(b), R^(b′), arehydrogen, R³ is H, lower alkyl or aryl.

Another preferred group of compounds of the present invention includesthose compounds of formula I, wherein Ar¹ is halogenophenyl,hydroxyphenyl, alkoxy phenyl, X is O, R¹ is hydrogen, m is 1, n is 0, 1or 2, Ar² is thienylene or phenylene group, preferably a thienylenegroup, and either R^(a) or R^(a′) forms a 5-6 membered ring with R³, orR^(a) forms a 5-6 membered ring with R^(a′) and R³ is H, lower alkyl oraryl.

In a further preferred group of compounds according to formula I, Ar¹ is4-chlorophenyl, X is O, R¹ is hydrogen, m is 1, n is 0, 1 or 2, Ar² isthienylene or phenylene group, preferably a thienylene group, and R^(a),R^(a′), R^(b), R^(b′) are hydrogen, R³ is H, lower alkyl or aryl and R⁴is H or C₁-C₁₀-alkyl or Aryl C₁-C₁₀-Alkyl, preferably hexyl or benzylgroup.

Said aryl or heteroaryl groups may optionally be substituted by halogen,hydroxy, nitro, sulfonyl (e.g. trifluoromethylsulfonyl groups), C₁-C₆alkyl or C₁-C₆ fluoroalkyl.

Compounds of formula I with proviso are believed to be novel and form anaspect of the invention.

Compounds of formula I, without proviso may be used for the treatment ofa disease.

Specifically, the compounds of formula I are suitable for use intreating disorders of the immune system and neuronal system of mammals,notably of human beings.

Such neuronal system disorders include for example neurodegenerativediseases e.g. Alzheimer's disease, Huntington's disease, Parkinson'sdisease, retinal diseases, spinal cord injury, multiple sclerosis, headtrauma, epilepsy and seizures, ischemic and hemorragic brain strokes.

Immune system disorders include for example asthma, transplantrejection, inflammatory processes such as inflammatory bowel disease(EBD), cartilage and bone erosion disorders, rheumatoid arthritis,septic shock.

The compounds according to formula I are also suitable for use intreating cancers, such as breast, colorectal, pancreatic, prostate,testicular, ovarian, lung, liver and kidney cancers.

In another embodiment, the compounds according to formula I may be usedfor treating cardiovascular diseases including atherosclerosis,restenosis, stroke, ischemia, e.g. cerebral ischemia, myocardialinfarction.

In another embodiment, the compounds according to formula I may be usedfor treating various ischemic conditions including heart and kidneyfailures, hepatic disorders and brain reperfusion injuries.

Preferably, the compounds according to formula I, alone or in the formof a pharmaceutical composition, are useful for the modulation of theJNK pathway, more specifically for treatment or prevention of disordersassociated with expression or activity of JNK, notably of JNK2 and -3.Said modulation usually preferably involves the inhibition of the JNKpathways, notably of the JNK2 and/or -3. Such an abnormal expression oractivity of JNK may be triggered by numerous stimuli (e.g. stress,septic shock, oxidative stress, cytokines) and may cause a cascade ofprocesses, leading to, for example, uncontrolled apoptosis, inflammatoryresponses or oncogenic processes. These phenomena are frequentlyinvolved in various disorders including the above enumerated disordersand disease states. Hence, the compounds according to the invention maybe used for the treatment of disorders by modulating the JNK function orsignaling pathways. The modulation of the JNK function or pathways mayinvolve its activation, but preferably it involves the down-regulationup to inhibition of the JNK pathways, notably of JNK1 and/or -2 and/orJNK3. The compounds of the invention may be employed alone or incombination with further pharmaceutical agents, e.g. with a further JNKmodulator.

When employed as pharmaceuticals, the sulfonamide derivatives of thepresent invention are typically administered in the form of apharmaceutical composition. Pharmaceutical compositions comprising acompound of formula I and a pharmaceutically acceptable carrier, diluentor excipient are also within the scope of the present invention. Aperson skilled in the art is aware of a whole variety of such carriers,diluents or excipients suitable to formulate a pharmaceuticalcomposition.

The compounds according to formula I, together with a conventionallyemployed adjuvant, carrier, diluent or excipient may be formulated aspharmaceutical compositions and unit dosages, and in such form may beemployed as solids, such as tablets or filled capsules, or liquids suchas solutions, suspensions, emulsions, elixirs, or capsules filled withthe same, all for oral use, or in the form of sterile injectablesolutions for parenteral (including subcutaneous) use. Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. When employed aspharmaceuticals, the sulfonamides derivatives of this invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound. Generally,the compounds of this invention are administered in a pharmaceuticallyeffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

The pharmaceutical compositions of these inventions can be administeredby a variety of routes including oral, rectal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Depending onthe intended route of delivery, the compounds are preferably formulatedas either injectable or oral compositions. The compositions for oraladministration can take the form of bulk liquid solutions orsuspensions, or bulk powders. More commonly, however, the compositions,are presented in unit dosage forms to facilitate accurate dosing. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a pre-determined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient. Typical unit dosage forms include pre-filled,pre-measured ampoules or syringes of the liquid compositions or pills,tablets, capsules or the like in the case of solid compositions. In suchcompositions, the sulfonamide compound is usually a minor component(from about 0.1 to about 50% by weight or preferably from about 1 toabout 40% by weight) with the remainder being various vehicles orcarriers and processing aids helpful for forming the desired dosingform.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the sulfonamide compound of formula I insuch compositions is typically a minor component, frequently rangingbetween 0.05 to 10% by weight with the remainder being the injectablecarrier and the like.

The above described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 8 of (29).

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in (29).

Still a further object of the present invention is a process forpreparing the sulfonamide derivatives according to formula I. Thesulfonamides of this invention may be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred experimentalconditions (i.e., reaction temperatures, time, moles of reagents,solvents, etc.) are given, other experimental conditions can also beused unless otherwise stated. Optimum reaction conditions may vary withthe particular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Synthesis of Compounds of the Invention:

The novel sulfonamide derivatives can be prepared from readily availablestarting materials. Three examples of synthetic pathways for thesulfonamides of formula I will be described.

The following abbreviations refer respectively to the definitions below:

AMEBA: (4-formyl-3-methoxyphenoxymethyl)polystyreneBoc: Tert.butyloxy-carbonyl

DCE: Dichloroethane DCM: Dichlioromethane DMA: Dimethylacetamide DMF:Dimethylformamide DMSO: Dimethylsulfoxide

EDTA: Ethylenediaminetetraacetic acid

Fmoc: Fluorenylmethyloxy-carbonyl NMP: N-methylpyrrolidone TFA:Tri-Fluoro Acetic Acid THF: Tetrahydrofuran TLC: Thin LayerChromatography TMOF: Trimethylorthoformate Protocol I:

A preferred pathway starts with compounds of formula II wherein R^(a),R^(a′), R^(b), R^(b′), R², R³, n and p are as defined for formula I andP is an amine protecting group.

The mono-protected diamines of formula II are either known compounds,commercially available or they can be prepared from known compounds byconventional procedures. Typical examples of compounds of formula IIcomprise ethylenediamine, propylenediamine, (n- or t-)-butylenediamine,1-amino-piperidine, aminomethylpiperidine.

In formula II, typical amine protecting groups P are the followingmoieties: carbobenzoxy (Cbz), fluorenylmethyloxy-carbonyl (finoc),allyloxycarbonyl,(2S)-2-([[1-(3,5-dimethoxyphenyl)-1-Methyl-ethoxy]-carbonyl], benzyl,1,1,1-triphenylmethyl, most preferably tert.butyloxy-carbonyl (Boc).Other amine protecting groups will be known to the synthetic chemist(30).

Generally, such mono protected diamines are reacted with sulfonylchlorides of formula III in the presence of a base as scavengeraccording to scheme I to lead to sulfonamides having the structuredisplayed in formula IV.

The above reaction may be conducted in the presence of anon-nucleophilic base such as triethylamine, di-isopropylethylamine,potassium carbonate and the like in an aprotic solvent such asN,N-dimethyl-formamide, dimethylsulfoxide, N-methylpyrrolidone,acetonitrile, chloroform, dichloroethane or dichloromethane at atemperature from about 0° to about 100° C., preferably 20-60° C.

The sulfonyl chlorides of formula III used for the preparation of thesulfonamides of formula IV may be prepared using conventionalsulfonylation methods using preferably chlorosulfonic acid assulfonating reagent. Typically, the sulfonylation reaction is performedby treating the carboxamide of formula V with about 5 to about 10 molarequivalent of the sulfonating reagent in an inert solvent, such asdichloromethane, at a temperature ranging from about −70° C. to about50° C.

Preferably, the addition of chlorosulfonic acid takes place at −70° C.and leads to the formation of the intermediate sulfonic acid. Increasingthe temperature to 20° C. allows the formation of the sulfonyl chlorideof formula III. In those cases in which a mixture of sulfonatedcompounds is obtained, sulfonylchloride of formula III can be isolatedby appropriate techniques such as flash chromatography orcrystallisation.

Carboxamides of formula V (X═O) can be prepared by methods known to theskilled practitioner, for example by reaction of an amine (for examplethien-2-yl methylamine, thien-2-yl ethylamine, furan-2-yl-methylamine orpyridyl-2-yl-methylamine) with an aroyl halide (for example4-chloro-benzoylchloride, pyridinyl-benzoylchloride). Thiocarboxamidesof formula V (X═S) can be obtained by methods known to the skilledpractitioner, for example by treatment of a carboxamide of formula Vwith Lawesson's reagent (31).

Sulfonamide compounds of formula IV can also be obtained starting frommono-protected diamines of formula II, using solid phase methodologies,for example using polymer-bound reagents, such as polymer-boundtriethylamine, di-isopropylethylamine, N-methylmorpholine, piperidine.Typically the sulfonylchloride of formula III is used in 1 to 5equivalents excess of the corresponding monoprotected diamine of formulaII. Ultimately the remaining excess of sulfonylchloride is trapped usingpolymer-bound primary amines such as amino-methyl polystyrene ortrisamine. Pure sulfonamide is obtained upon filtration of the resins.

Subsequent removal of the protecting group, P, in the formula IV, usingdeprotection methods known in the art (30), leads to the primary orsecondary amines of formula VI or the corresponding ammonium salt,depending on the applied deprotection protocol.

The ammonium salt of the amine of formula VI may be neutralized in thepresence of a base such as triethyl-amine, di-isopropylethylamine, orN-methylmorpholine. The alkylation of the amine moiety of formula VIinto an amine of formula I is achieved via the reductive amination of analdehyde or a ketone: the amine of formula VI is reacted with thedesired aldehyde or ketone of formula VII wherein R⁵ and R⁶ are asdefined for formula I.

Typical examples of ketones and aldehydes of formula VII areC₁-C₁₀-aldehydes/ketones and ketones of the type Ph-C(O)—(C₁-C₆)alkyl.Depending whether the amine of formula VI is a primary or a secondaryamine, a corresponding imine or iminium ion is preformed which may beisolated, or reduced in situ. In the case of primary amines as startingmaterial, the intermediate imine may be isolated to avoid furtheralkylation. The imine intermediate is reduced with a suitable reducingagent such as sodium borohydride, sodium cyanoborohydride, hydrogen inthe presence of Pd. A preferred reducing agent is sodium triacetoxyborohydride. Reduction of imines is favored when the imine isprotonated, so the pH may be adjusted during reduction, for example byaddition of acetic acid. Reductive amination is discussed in (32).

Sulfonamides of formula I can also be obtained from amines of formula VIor their ammonium salts using polymer-bound reagents. Polymer-bound basesuch as polymer-bound triethylamine, di-isopropylethylamine,N-methylmorpholine, piperidine may be used to neutralize the ammoniumsalt of amine VI. For the reductive amination, the appropriate aldehydeor ketone of formula VII may be used in 0.9 equivalents. Polymer-boundreducing agents such as polymer-bound sodium borohydride, sodiumcyanoborohydride, sodium triacetoxy borohydride are used to reduce theintermediate imine to an amine of formula I. Excess amine of formula VIcan be trapped using AMEBA aldehyde resin. Sulfonamides of formula I canthen be obtained upon filtration of the resins.

Protocol II:

Another preferred pathway starts with compounds of formula VIII whereinR^(a), R^(a′), R^(b), R^(b′), R², R³, n and p are as defined for formulaI, and P is an amine protecting group. The mono-protected diamines offormula VIII are either known compounds, commercially available or theycan be prepared from known compounds by conventional procedures.

In formula VIII, the typical amine protecting groups, P, may be selectedfrom the following moieties: carbobenzoxy (Cbz),fluorenylmethyloxy-carbonyl (fmoc), allyloxycarbonyl,(2S)-2-([[1-(3,5-dimethoxyphenyl)-1-methylethoxy]-carbonyl], benzyl,1,1,1-triphenylmethyl, most preferably tert.butyloxy-carbonyl (Boc).Other amine protecting groups will be known for the synthetic chemist(30).

Alkylation of the amine of formula VIII is achieved via the reactionwith an aldehyde or a ketone of formula VII through reductive amination,leading to an amine of formula IX as follows:

The amine of formula VIII is reacted with the appropriate aldehyde orketone of formula VII, if necessary in the presence of a nonnucleophilic base such as triethylamine, di-isopropylethylamine, orN-methylmorpholine to ensure some of the amine is deprotonated, in anpolar solvent such as DCE, ThF, TMOF, DMF, DMA, DCM, methanol, NMP. Theintermediate imine derivative may be reduced in situ or isolated uponevaporating the solvent, and reduced in a separate reaction. In the caseof primary amines as starting material, the intermediate imine may beisolated to avoid further alkylation. Reduction of imines is favoredwhen the imine is protonated, so the pH may be adjusted duringreduction, for example by addition of acetic acid. Reduction of theimine derivative is performed with a suitable reducing agent such assodium borohydride, sodium cyanoborohydride, hydrogen in the presence ofPd, most preferably sodium triacetoxy borohydride. Preferred solventsare DCE, THF, TMOF, DMF, DMA, DCM, methanol, NMP.

Amines of formula IX can also be obtained via solid phase synthesisusing polymer-bound reagents. Polymer-bound reducing agents such aspolymer-bound sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxy borohydride are used to reduce the imine to the correspondingamine of formula IX. Excess of amine VIII can be removed using AMEBAaldehyde resin. Amines of formula VIII can then be obtained uponfiltration of the resins.

Subsequent removal of the protecting group P in formula IX, usingdeprotection methods known to the skilled practitioner, as mentionedabove, leads to the corresponding amine X.

Amine X may be obtained as the corresponding ammonium salt depending onthe applied deprotection technique used.

Ultimately, such amines or ammonium salts are reacted withsulfonylchlorides of formula III in the presence of a base as scavengerto obtain sulfonamides shown in formula I.

The reaction is generally conducted in the presence of anon-nucleophilic base such as triethylamine, diisopropylethylamine,potassium carbonate and the like in an aprotic solvent such asN,N-dimethyl-formamide, dimethylsulfoxide, N-methylpyrrolidone,acetonitrile, chloroform, dichloroethane or dichloromethane at atemperature from about 0° to about 100° C., preferably 20-60° C. In caseof ammonium salts of formula X the reaction should be performed inexcess of scavenger base.

Sulfonamide I can also be synthesised via a solid phase synthesis routeusing polymer-bound reagents, such as polymer-bound triethylamine,di-isopropylethylamine, N-methylmorpholine, piperidine, carbonate.Typically the sulfonylchloride III is used in 1 to 1.5 equivalentsexcess of the corresponding amine VIII. Ultimately the remaining excessof sulfonylchloride is trapped using polymer-bound primary amines suchas aminomethyl polystyrene or trisamine. Pure sulfonamide I is obtainedupon filtration of the resins.

In the case of compounds of formula I where R⁴ is H, the mode ofsynthesis could follow the protocol I and the process would stop oncethe compound VI is formed. Compounds of formula VI then represent asubset of compounds of formula I.

For the formation of compounds of formula I wherein R³ is an aromaticmoiety, Protocol III should be used.

Protocol III:

A sulfonyl chloride of formula III is reacted with an aminoalcohol offormula XI to obtain an alcohol of formula XII. The reaction isconducted in a polar solvent such as DMF or THF. Any excess of amine isextracted into an acidic aqueous phase

After solvent evaporation, the alcohol of formula XII is submitted tooxidation with an oxidizing agent e.g. pyridine N-oxide to yield to analdehyde of formula XIII.

The aldehyde of formula XIII is subjected to a reductive anination suchas already described in Protocol I or II. In this case, an aldehyde offormula XIII is reacted with an aromatic amine of formula XIV in anpolar solvent such as DCE, THF, TMOF, DMF, DMA, DCM, methanol, NMP tolead to an amine of formula I. The intermediate imine may be reduced insitu or isolated upon evaporating the solvent, and reduced in a separatereaction. Formation of the imine may be favored by adjusting the pH tomildly acidic to neutral, for example, by addition of acetic acid or ifnecessary a small quantity of base. Reduction of the imine derivative isperformed with a suitable reducing agent such as sodium borohydride,sodium cyanoborohydride, hydrogen in the presence of Pd, most preferablysodium triacetoxy borohydride. Preferred solvents are DCE, ThF, TMOF,DMF, DMA, DCM, methanol, NMP.

If the above set out general synthetic methods are not applicable forobtaining certain compounds of formula I, suitable methods ofpreparation known by a person skilled in the art should be used.

EXAMPLES

The invention will be illustrated by means of the following exampleswhich are not to be construed as limiting the scope of the invention.

The compounds of the present invention may be synthesized according tothe different synthesis pathways provided above. The following examplesillustrate preferred methods for synthesizing the compounds according toformula I and determining their activities.

Example I5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonylchloride (1b) (compound of formula III) a)4-Chloro-N-thiophen-2-ylmethyl-benzamide (1a)

A solution of 4-chlorobenzoyl chloride (0.114 mol) in 50 mL dry CH₂Cl₂was added over 30 min to a stirred solution of 2-aminomethyl-thiophene(0.137 mol) and ^(i)Pr₂NEt (0.25 mol) in CH₂Cl₂ (200 mL) at 0° C. Awhite solid was formed and the reaction was allowed to warm to roomtemperature over 1 h. The mixture was diluted with 200 mL of CH₂Cl₂,washed twice with HCl aq. (0.1N) and dried over MgSO₄. Evaporation ofthe solvents afforded 28 g (98%) of the title benzamide (1a) as a whitesolid: m.p. 153-54° C., ¹H NMR (CDCl₃) δ 7.9 (d, J=8.67 Hz, 2H), 7.58(d, J=8.67 Hz, 2H), 7.44 (dd, J=3.77, 1.13 Hz, 1H), 7.22 (d, J=5.27 Hz,1H), 7.16 (dd, J=3.39, 5.27 Hz, 1H), 6.62 (br d, 1H), 4.98 (d, J=5.65Hz, 2H).

b)5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonylchloride (1b)

Chlorosulfonic acid (20.1 mL, 198 mmol) in CH₂Cl₂ (80 mL) was addeddropwise to a solution of the above compound (1a) (10 g, 40 mmol) inCH₂Cl₂ (500 mL) at −80° C. The mixture was allowed to reach roomtemperature in 5 h. The reaction mixture was poured on ice and quicklyextracted with CH₂Cl₂. The organic layer was dried over MgSO₄ and thesolvent was evaporated to dryness which afforded 8.8 g (63%) of desiredsulfonyl chloride (1b); mp 133-35° C., ¹H NMR (DMSO-d6) δ 9.21 (t, J=6.4Hz, 1H), 7.87 (d, J=8.67 Hz, 2H), 7.53 (d, J=8.67 Hz, 2H), 6.91 (d,J=3.39 Hz, 1H), 6.77 (d, J=3.39 Hz, 1H), 4.53 (d, J=3.77 Hz, 2H).

Example II4-Chloro-N-{5-[1-(4-trifluoromethyl-benzyl)-piperidin-3-ylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(2)

The synthesis of the above compound (2) is a 3-step-synthesis (seescheme I).

Protocol I: Step 1-N-Sulfonylation (Compound of Formula IV)

The mono protected diamine (+/−)-3-Amino-1-N-Boc-Piperidine (compound offormula II) (0.4 g, 2 mMol, 1 eq),5-(4-chlorobenzamidomethyl)thiophene-2-sulphonyl chloride (1b) (compoundof formula III) (0.99 g, 2.4 mMol, 1.2 eq), and piperidine resin (2 g,1.5 eq, loading of 1.5 mMol/g) are swirled in THF (50 ml) on orbitalshaker overnight. Aminomethyl polystyrene (1.82 g, 1 eq, loading of 1.1mMol/g) is added to the flask and contents swirled on orbital shakerovernight.

The resins are filtered and washed with a further 50 ml of THF.Filtrates are combined and solvent is evaporated under reduced pressureto yield quantitatively the corresponding sulfonamide (formula IV). Nofurther purification is required at this stage.

Step 2—Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide from Step 1 is loaded into a round bottomed flask anddissolved in 50% TFA/DCM (50 ml). The flask is swirled on orbital shakeruntil completion of the reaction is confirmed by TLC.

The solvent is evaporated under reduced pressure to yield TFA ammoniumsalt.

The salt dissolved in methanol (50 ml), Carbonate resin (2.67 g, 2 eq,loading of 1.5 mMol/g) is added and the contents are swirled on orbitalshaker over night.

The resin is filtered and washed with a further 50 ml of methanol.Filtrates are combined and the solvent is evaporated under reducedpressure to yield quantitatively the free amine. No purification isrequired at this stage.

Step 3—Reductive Amination (Compound of Formula I)

A round bottomed flask is charged with the free amine from Step 2 (0.41g, 1 mMol, 1 eq), the aldehyde 4-(Trifluoromethyl)-Benzaldehyde (0.16 g,0.9 mMol, 0.9 eq), and glacial acetic acid (60 μl, 1 mMol, 1 eq).Methanol (30 ml) is added and the flask is swirled on orbital shakerovernight.

Borohydride resin (0.67 g, 2 eq, loading of 2.5 mMol/g) is added toflask and contents are swirled on orbital shaker overnight.

AMEBA (aldehyde) resin (0.46 g, 0.5 eq, loading of 0.9 mMol/g) is addedto flask and contents swirled on orbital shaker overnight.

The resins are filtered off and washed with a further 30 ml of methanol,and filtrates are combined and solvent is evaporated under reducedpressure to yield the crude product. The crude product is purified bypreparative HPLC using acetonitrile and water as eluents to obtain thepure4-Chloro-N-{5-[1-(4-trifluoromethyl-benzyl)-piperidin-3-ylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(2).

Example III4-Chloro-N-{5-[2,2-dimethyl-3-(4-trifluoromethyl-benzylamino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(3)

The synthesis of the above compound (3) is a 3-step-synthesis andfollows the above detailed protocol (Protocol I):

Step 1—N-Sulfonylation (Compound of Formula IV)

In this case the mono-protected diamine used is the1-Boc-Amino-2,2-Dimethyl-1,3-Propanediamine.

Step 2—Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Animation (Compound of Formula I)

The free amine obtained through the above step 2 is reacted in this casewith 4-(Trifluoromethyl)-Benzaldehyde. The final product afterpurification is4-Chloro-N-{5-[2,2-dimethyl-3-(4-trifluoromethyl-benzylamino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(3).

Example IV4-Chloro-N-(5-{3-[methyl-(4-trifluoromethyl-benzyl)-amino]-propylsulfamoyl}-thiophen-2-Ylmethyl)-benzamide(4)

The synthesis of the above compound (4) is a 3-step-synthesis andfollows the above detailed protocol (Protocol I):

Step 1—N-Sulfonylation (Compound of Formula IV)

In this case the mono-protected diamine used is theN-(3-Aminopropyl)-N-Methylcarbamic Acid Tert-Butyl Ester.

Step 2—Removal of N-Boc-Protection (Compound of Formula VI)

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Amination (Compound of Formula I)

The free amine obtained through the above step 2 is reacted in this casewith 4-(Trifluoromethyl)-Benzaldehyde. The final product afterpurification is4-Chloro-N-(5-{3-[methyl-(4-trifluoromethyl-benzyl)-amino]-propylsulfamoyl}-thiophen-2-ylmethyl)-benzamide(4).

Example V4-Chloro-N-{5-[3-(hexyl-methyl-amino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(5)

The synthesis of the above compound (5) is a 3-step-synthesis andfollows the above detailed protocol (Protocol I):

Step 1—N-Sulfonylation (Compound of Formula IV)

In this case the monoBoc diamine used is theN-(3-Aminopropyl)-N-Methylcarbamic Acid Tert-Butyl Ester.

Step 2—Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Amination (Compound of Formula I):

The free amine obtained through the above step 2 is reacted in this casewith 1-Hexanal. The final product after purification is4-Chloro-N-{5-[3-(hexyl-methyl-amino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(5).

Example VI4-Chloro-N-{5-[2-(4-trifluoromethyl-benzylamino)-cyclohexylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(6)

The synthesis of the above compound (6) is a 3-step-synthesis andfollows the above detailed protocol (Protocol I):

Step 1—N-Sulfonylation (Compound of Formula IV)

In this case the mono-protected diamine used is the1-Boc-Amino-2-Aminocyclohexane.

Step 2—Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Amination (Compound of Formula I)

The free amine obtained through the above step 2 is reacted in this casewith 4-(Trifluoromethyl)-Benzaldehyde. The final product afterpurification is of4-Chloro-N-{5-[2-(4-trifluoromethyl-benzylamino)-cyclohexylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(6).

Example VII4-Chloro-N-[5-(2-hexylamino-ethylsulfamoyl)-thiophen-2-ylmethyl]-benzamide(7)

The synthesis of the above compound (7) is a 3-step-synthesis andfollows the above detailed protocol (Protocol I):

Step 1—Sulfonylation (Compound of Formula IV)

In this case the mono-protected diamine used is the1-Boc-Amino-Ethylenediamine.

Step 2—Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Amination (Compound of Formula I)

The free amine obtained through the above step 2 is reacted in this casewith 1-Hexanal. The final product after purification is4-Chloro-N-[5-(2-hexylamino-ethylsulfamoyl)-thiophen-2-ylmethyl]-benzamide(7).

Example VIII4-Chloro-N-{5-[1-(4-trifluoromethyl-benzyl)-piperidin-4-ylsulfamoyl]thiophen-2-ylmethyl}-benzamide(8)

The synthesis of the above compound (8) is a 3-step-synthesis andfollows the above detailed protocol (Protocol I):

Step 1—Sulfonamide Formation (Compound of Formula IV)

In this case the mono-protected diamine used is the4-Amino-1-Boc-Piperidine.

Step 2—Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Amination (Compound of Formula I)

The free amine obtained through the above step 2 is reacted in this casewith 4-(Trifluoromethyl)-Benzaldehyde. The final product afterpurification is4-Chloro-N-{5-[1-(4-trifluoromethyl-benzyl)-piperidin-4-ylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(8).

Example IX 4-Chloro-N-[5-(3-hexylamino-2,2-dimethylpropylsulfamoyl)-thiophen-2-ylmethyl]-benzamide (9) The synthesis of theabove compound (9) is a 3-step-synthesis and follows the above detailedprotocol (Protocol I):

Step 1—Sulfonylation (Compound of Formula IV)

In this case the mono-protected diamine used is the1-Boc-Amino-2,2-Dimethyl-1,3-Propanediamine.

Step 2-Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Amination (Compound of Formula I)

The free amine obtained through the above step 2 is reacted in this casewith 1-Hexanal. The final product after purification is4-Chloro-N-[5-(3-hexylamino-2,2-dimethylpropylsulfamoyl)-thiophen-2-ylmethyl]-benzamide (9).

Example X4-Chloro-N-{5-[3-(4-trifluoromethyl-benzylamino)-benzylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(10)

The synthesis of the above compound (10) is a 3-step-synthesis andfollows the above detailed protocol (Protocol I):

Step 1—Sulfonylation (Compound of Formula IV)

In this case the mono-protected diamine used is3-(aminomethyl)-1-N-Boc-aniline

Step 2—Removal of N-Boc-Protection (Compound of Formula VI):

The sulfonamide obtained through the above step 1 is N-Boc deprotectedto give the corresponding free amine.

Step 3—Reductive Amination (Compound of Formula I

The free amine obtained through the above step 2 is reacted in this casewith 4-(Trifluoromethyl)-Benzaldehyde. The final product afterpurification is4-Chloro-N-{5-[3-(4-trifluoromethyl-benzylamino)-benzylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(10).

The following compounds were prepared on a parallel fashion according tothe generic procedure (Protocol I) described above.

The following table provides HPLC data and mass spectroscopy data of thementioned examples.^(1,2).

Ex- am- HPLC¹ Mass² Mass² ple Name (Rt mn) M + 1 M − 1 24-Chloro-N-{5-[1-(4-trifluoromethyl- 4.91 572 570benzyl)-piperidin-3-ylsulfamoyl]- thiophen-2-ylmethyl}-benzamide 34-Chloro-N-{5-[2,2-dimethyl-3-(4- 3.77 574 572trifluoromethyl-benzylamino)- propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide 4 4-Chloro-N-(5-{3-[methyl-(4- 3.62 560 558trifluoromethyl-benzyl)-amino]- propylsulfamoyl}-thiophen-2-ylmethyl)-benzamide 5 4-Chloro-N-{5-[3-(hexyl-methyl- 3.48 486 484amino)-propylsulfamoyl]-thiophen-2- ylmethyl}-benzamide 64-Chloro-N-{5-[2-(4-trifluoromethyl- 3.78 586 584benzylamino)-cyclohexylsulfamoyl]- thiophen-2-ylmethyl}-benzamide 74-Chloro-N-[5-(2-hexylamino- 3.38 458.1 456 ethylsulfamoyl)-thiophen-2-ylmethyl]-benzamide 8 4-Chloro-N-{5-[1-(4-trifluoromethyl- 3.62 572 570benzyl)-piperidin-4-ylsulfamoyl]- thiophen-2-ylmethyl}-benzamide 94-Chloro-N-[5-(3-hexylamino-2,2- 3.68 500 498dimethyl-propylsulfamoyl)-thiophen- 2-ylmethyl]-benzamide 104-Chloro-N-{5-[3-(4-trifluoromethyl- 5.83 594 592benzylamino)-benzylsulfamoyl]- thiophen-2-ylmethyl}-benzamide ¹HPLCconditions: C8 Symmetry a-MeCN, 0.09% TFA, 0 to 100% (8 min) ²Massspectrum APCI

Example XI4-Chloro-N-{5-[3-(4-trifluoromethyl-benzylamino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(11)

The synthesis of the above compound (11) is a 3-step-synthesis andfollows the below detailed protocol (Protocol II):

Protocol II: Step 1—Reductive Amination (Compound of Formula IX)

A round bottomed flask is charged with the mono-protected diamine(compound of formula VII), N-(3-Aminopropyl)-N-Methylcarbamic AcidTert-Butyl Ester, (1 mMol, 1 eq), an aldehyde of formula VII,4-(Trifluoromethyl)-Benzaldehyde (0.9 mMol, 0.9 eq), and glacial aceticacid (60 μl, 1 mMol, 1 eq). Methanol (30 ml) is added and the flask isswirled on an orbital shaker overnight.

Borohydride resin (0.67 g, 2 eq, loading of 2.5 mMol/g) is added to theflask and the contents are swirled on orbital shaker overnight.

AMEBA (aldehyde) resin (0.46 g, 0.5 eq, loading of 0.9 mMol/g) is addedto flask and contents are swirled on an orbital shaker overnight.

All resins are filtered and washed with a further 30 ml of Methanol,filtrates are combined and the solvent is evaporated under reducedpressure to yield product. The resulting 3-Boc-Aminomethyl-Piperidinealkylated amine (compound of formula IX) is used without purificationfor further reactions.

Step 2—Removal of N-Boc-Protection (Compound of Formula X)

The mono-protected mono-alkyl diamine obtained in Step 1 is loaded intoa 100 ml round bottomed flask and dissolved in 50% TFA/DCM (50 ml). Theflask is swirled on an orbital shaker until the reaction is complete aschecked by TLC.

The solvent is evaporated under reduced pressure to yield the TFAammonium salt. The salt is dissolved in Methanol (50 ml), Carbonateresin (2.67 g, 2 eq, loading of 1.5 mMol/g) is added to the flask andthe contents are swirled on an orbital shaker overnight.

The resin is filtered and washed with further 50 ml Methanol. Combinedfiltrates are evaporated under reduced pressure to yield the freemonoalkyl diamine (formula X). No purification is required at thisstage.

Step 3—N-Sulfonylation (Compound of Formula I)

A round bottomed flask is charged with the monoalkyl-diamine obtainedfrom Step 2 (0.25 g, nMol, 1 eq),5-(4-chlorobenzamidomethyl)thiophene-2-sulphonyl chloride, (1b) (0.42 g,1.2 mMol, 1.2 eq), and piperidine resin (1 g, 1.5 eq, loading of 1.5mMol/g) in THF (50 ml). The flask is swirled on an orbital shakerovernight.

Aminomethyl polystyrene (0.91 g, 1 eq, loading of 1.1 mMol/g) is addedto the flask and the contents are swirled on orbital shaker overnight.

The resins are filtered off and washed with a further 50 ml of THF.Filtrates are combined and solvent is evaporated under reduced pressureto yield crude product. The crude product is purified by preparativeHPLC using Acetonitrile and water as eluents leading to compound (11),4-Chloro-N-{5-[3-(4-trifluoromethyl-benzylamino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide.

Example XII4-Chloro-N-(5-{[1-(4-trifluoromethyl-benzyl)-piperidin-3-ylmethyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide(12)

The synthesis of the above compound (12) is a 3-step-synthesis andconsists in the above detailed protocol (see scheme II):

Step 1—Reductive Amination (Compound of Formula IX)

The mono-protected diamine used is 3-Boc-Aminomethyl-Piperidine and thealdehyde is 4-(Trifluoromethyl)-Benzaldehyde.

Step 2—Removal of N-Boc-Protection (Compound of Formula X)

The mono-protected mono-alkyl diamine obtained in Step 1 is deprotectedto obtain the corresponding free amine.

Step 3—N-Sulfonylation (Compound of Formula I)

The free amine from step 2 is reacted with compound (1b) to yield tocompound (12),4-Chloro-N-(5-{[1-(4-trifluoromethyl-benzyl)-piperidin-3-ylmethyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide.

Example XIII4-Chloro-N-(5-{methyl-[3-(4-trifluoromethyl-benzylamino)-propyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide(13)

The synthesis of the above compound (12) is a 3-step-synthesis andfollows the above detailed protocol (Protocol II):

Step 1—Reductive Amination (Compound of Formula IX)

The mono-protected diamine used is 1-Boc-Amino-1,3-Propanediamine andthe aldehyde is 4-(Trifluoromethyl)-Benzaldehyde.

Step 2—Removal of N-Boc-Protection (Compound of Formula X)

The mono-protected mono-alkyl diamine obtained in Step 1 is deprotectedto obtain the corresponding free amine.

Step 3-N-Sulfonylation (Compound of Formula I)

The free amine from step 2 is reacted with compound (1b) to yield to4-Chloro-N-(5-{methyl-[3-(4-trifluoromethyl-benzylamino)-propyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide(13).

Example XIV4-Chloro-N-{5-[(3-hexylamino-propyl)-methyl-sulfamoyl]-thiophen-2-ylmethyl}-benzamide(14)

The synthesis of the above compound (14) is a 3-step-synthesis andfollows the above detailed protocol (Protocol II):

Step 1—Reductive Amination (Compound of Formula IX)

The mono-protected diamine used is N-(3-Aminopropyl)-N-MethylcarbamicAcid Tert-Butyl Ester and the aldehyde is 1-Hexanal.

Step 2-Removal of N-Boc-Protection (Compound of Formula X)

The mono-protected mono-alkyl diamine obtained Step 1 is deprotected toobtain the corresponding free amine.

Step 3-N-sulfonylation (Compound of Formula I)

The resulting free amine from step 2 is reacted with compound (1b) toyield to4-Chloro-N-{5-[(3-hexylamino-propyl)-methyl-sulfamoyl]-thiophen-2-ylmethyl}-benzamide(14).

Example XV4-Chloro-N-(5-{[1-(4-trifluoromethyl-benzyl)-pyrrolidin-2-ylmethyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide(15)

The synthesis of the above compound (15) is a 3-step-synthesis andfollows the above detailed protocol (Protocol II):

Step 1—Reductive Amination (Compound of Formula IX)

The mono-protected diamine used is2-(N-Tert-Butoxycarbonylaminomethyl)-Pyrrolidine and the aldehyde is4-(Trifluoromethyl)-Benzaldehyde.

Step 2—Removal of N-Boc-Protection (Compound of Formula X)

The mono-protected mono-alkyl diamine obtained in Step 1 is deprotectedto obtain the corresponding free amine.

Step 3-N-Sulfonation (Compound of Formula I)

The resulting free amine from step 2 is reacted with compound (1b) toyield to4-Chloro-N-(5-{[1-(4-trifluoromethyl-benzyl)-pyrrolidin-2-ylmethyl]-sulfamoyl}-thiophen-2-ylmethyl)-benzamide(15).

The following compounds were prepared according to the generic procedure(protocol II) described above

The following table provides HPLC data and mass spectroscopy data of thementioned examples.^(1,2).

Ex- am- HPLC¹ Mass² Mass² ple Name (Rt mn) M + 1 M − 1 114-Chloro-N-{5-[3-(4-trifluoromethyl- 3.58 546 544benzylamino)-propylsulfamoyl]- thiophen-2-ylmethyl}-benzamide 124-Chloro-N-(5-{[1-(4- 3.69 586 584 trifluoromethyl-benzyl)-piperidin-3-ylmethyl]-sulfamoyl}-thiophen- 2-ylmethyl)-benzamide 134-Chloro-N-(5-{methyl-[3-(4- 3.78 560 558 trifluoromethyl-benzylamino)-propyl]-sulfamoyl}-thiophen-2- ylmethyl)-benzamide 144-Chloro-N-{5-[(3-hexylamino- 3.65 486 484propyl)-methyl-sulfamoyl]-thiophen- 2-ylmethyl}-benzamide 154-Chloro-N-(5-{[1-(4- 3.6 572 570 trifluoromethyl-benzyl)-pyrrolidin-2-ylmethyl]-sulfamoyl}- thiophen-2-ylmethyl)-benzamide ¹HPLC conditions:C8 Symmetry a-MeCN, 0.09% TFA, 0 to 100% (8 min) ²Mass spectrum APCI

Example XVI4-Chloro-N-{5-[2,2-dimethyl-3-(3-trifluoromethanesulfonyl-phenylamino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide(16)

The synthesis of the above compound (16) is a 3-step-synthesis andconsists of the following protocol (see scheme III):

Step 1-Sulfonylation of an Aminoalcohol (Compound of Formula XII)

To a stirred solution of 2 equivalents of3-Amino-2,2-dimethyl-propan-1-ol (1.0 g, 10 mmol) in DMF in the presenceof 2 equivalents of DIEA (1.7 ml, 10 mMol) is added a solution ofsulfonylchloride (1b) (1.75 g, 5 mMol, 1 equivalent) in DMF. Thereaction mixture is stirred for 12 h at room temperature. DCM is addedand any excess of amine is extracted into 0.1N HCl solution. The organicphase is washed with brine and dried over MgSO₄.4-Chloro-N-[5-(3-hydroxy-2,2-dimethyl-propylsulfamoyl)-thiophen-2-ylmethyl]-benzamide(compound of formula XII) is obtained after evaporation of the solvent.LC-MS analysis and NM analysis showed that the compound was pure enoughto carry on the next step.

Step 2—Alcohol Oxidation (Compound of Formula XIII)

Compound of formula XII (954 mg, 2.3 mmol, 1.0 eq.) obtained from step 1was dissolved in 5 mL DMSO and Et₃N (3.0 eq.) was added to the mixture.Then, sulfur trioxide pyridine complex (3.0 eq.) dissolved in 10 mL ofDMSO was further added to the reaction mixture which was stirred at roomtemperature for 2.5 h (until complete disappearance of the alcohol byTLC). HCl (1M) was added and the product was extracted with ethylacetate. The organic phase was washed with HCl (1M) and then brine anddried with MgSO₄. The solvent was then evaporated. The aldehyde,4-Chloro-N-[5-(2,2-dimethyl-3-oxo-propylsulfamoyl)-thiophen-2-ylmethyl]-benzamide(compound of formula XIII) was then purified by column chromatographyusing Ethylacetate/DCM (1/1).

Step 3—Reductive Amination (Compound of Formula I)

A solution of4-Chloro-N-[5-2,2-diethyl-3-oxo-propylsulfamoyl)-thiophen-2-ylmethyl]-benzamide(formula XIII) obtained from step 2 (0.41 g, 1 mMol, 1 eq.) and3-((Trifluoromethyl)sulfonyl)-aniline (0.22 g, 1 mMol, 1 eq.) (formulaXIV) in Tetrachloroethylen is heated at 110° C. in the presence ofMolecular sieves 4 Å for 36 h. The reaction mixture is allowed to coolto room temperature and Sodiumcyanoborohydride (0.12 g, 2 mMol, 2 eq.)is added. The reaction is stirred for an additional 12 h at roomtemperature. The organic layer is washed with brine and dried overMgSO₄. The solvents are evaporated to dryness. The crude product ispurified by preparative HPLC using an Acetonitrile/water gradient toyield to pure compound (16),4-Chloro-N-{5-[2,2-dimethyl-3-(3-trifluoromethanesulfonyl-phenylamino)-propylsulfamoyl]-thiophen-2-ylmethyl}-benzamide.

The following table provides HPLC data and mass spectroscopy data of thementioned examples.^(1,2).

Ex- HPLC¹ Mass² Mass² ample Name (Rt mn) M + 1 M − 1 164-Chloro-N-{5-[2,2-dimethyl-3-(3- 5.51 624 622 trifluoromethanesulfonyl-phenylamino)-propylsulfamoyl]- thiophen-2-ylmethyl}-benzamide ¹HPLCconditions: C8 Symmetry a-MeCN, 0.09% TFA, 0 to 100% (8 min) ²Massspectrum APCI

Example XVII Preparation of a Pharmaceutical Formulation

The following formulation examples illustrate representativepharmaceutical compositions according to the present invention being notrestricted thereto.

Formulation 1—Tablets

A sulfonamide compound of formula I is admixed as a dry powder with adry gelatin binder in an approximate 1:2 weight ration. A minor amountof magnesium stearate is added as a lubricant. The mixture is formedinto 240-270 mg tablets (80-90 mg of active sulfonamide compound pertablet) in a tablet press.

Formulation 2—Capsules

A sulfonamide compound of formula I is admixed as a dry powder with astarch diluent in an approximate 1:1 weight ratio. The mixture is filledinto 250 mg capsules (125 mg of active sulfonamide compound percapsule).

Formulation 3—Liquid

A sulfonamide compound of formula I (1250 mg), sucrose (1.75 g) andxanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve,and then mixed with a previously prepared solution of microcrystallinecellulose and sodium carboxymethyl cellulose (1:89, 50 mg) in water.Sodium benzoate (10 mg), flavor, and color are diluted with water andadded with stirring. Sufficient water is then added to produce a totalvolume of 5 mL.

Formulation 4—Tablets

A sulfonamide compound of formula I is admixed as a dry powder with adry gelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into450-900 mg tablets (150-300 mg of active sulfonamide compound) in atablet press.

Formulation 5—Injection

A sulfonamide compound of formula I is dissolved in a buffered sterilesaline injectable aqueous medium to a concentration of approximately 5mg/mL.

Example XVIII Biological Assays Biological Results

The activities of the compounds according to formula I may be assessedusing the following in vitro and in vivo biological assays.

JNK2 and -3 In Vitro Assays:

The phosphorylation of c-jun by JNK2 or JNK3 can be followed bymonitoring the incorporation of ³³P into c-jun following the protocolbelow. The inhibitory activity of the compounds according to formula I,towards c-jun phosphorylation through JNK, is determined by calculatingphosphorylation activity in the presence or absence of compoundsaccording to formula I.

JNK3 and/or -2 assays are performed in 96 well MTT plates: incubation of0.5 μg of recombinant, pre-activated GST-JNK3 or GST-JNK2 with 1 μg ofrecombinant, biotinylated GST-c-Jun and 2 μM ³³γ-ATP (2 nCi/μl), in thepresence or absence of compounds according to formula I and in areaction volume of 50 μl containing 50 mM Tris-HCl, pH 8.0; 10 mM MgCl₂;1 mM Dithiothreitol, and 100 μM Na₃VO₄. The incubation is performed for120 min. at R.T and stopped upon addition of 200 μl of a solutioncontaining 250 μg of Streptavidine-coated SPA beads (Amersham, Inc.)*, 5mM EDTA, 0.1% Triton-X-100 and 50 μM ATP, in phosphate saline buffer.After incubation for 60 minutes at RT, beads are sedimented bycentrifugation at 1500×g for 5 minutes, resuspended in 200 μl of PBScontaining 5 mM EDTA, 0.1% Triton X-100 and 50 μM ATP and theradioactivity measured in a scintillation β counter, followingsedimentation of the beads as described above. By replacing biotinylatedGST-c Jun with biotinylated GST-₁ATF₂ or biotinylated myelin basicprotein, this assay can be used to measure inhibition of preactivatedp38 and ERK MAP Kinases, respectively.

The tested compounds according to formula I display an inhibition (IC₅₀)with regard to JNK3 of less than 10 μM, preferably less than 1 μM andmore preferred less than 0.25 μM. For instance compounds (13) and (14)display an inhibition (IC₅₀) with regard to JNK3 of 188 nM and 184 nMrespectively.

I1-2 Release Assay:

JNK pathway activation triggers the production of inflammatory cytokinessuch as IL-2. JNK can be activated by external stimuli such as PMA andIonomycine and IL-2 production can be measured via an IL-2 ELISA test.Comparative measurements with and without the compounds of the inventionaccording to the following protocol measure the ability of the compoundsto prevent to stress-mediated IL-2 release.

Jurkat cells, a human T cell leukemia cell line (American Type CultureCollection # TIB 152) were cultured in RPMI 1640 medium (Gibco, BRL)supplemented with 10% of heat-activated fetal calf serum (FCS),Glutamine and Penstrep. The cell suspension in the medium is diluted togive 2.10⁶ cells/mL. The cells were plated (2.10⁵ cells/well) on a96-well plate containing different concentrations of a compoundaccording to formula I (final concentration of compounds, 10, 3, 1, 0.3,0.1 μM). This mixture is incubated 30 minutes at 37° C. in a humidifiedCO₂ atmosphere. Cells were then treated with 10 μl PMA(Phorbolmyristate-13 Acetate-12)+Ionomycine (0.1 μM and 1 μM finalconcentration) in all wells except negative control. In wells withoutcompounds, 10 μl of RPMI 2% DMSO (=0.1% final) is added. Cells areincubated 24 hours at 37° C. and then the supernatant harvested (freezeat −20° C. if not used the same day) prior to performing IL-2 ELISA teston the supernatant.

IL-2 ELISA Assay:

IL-2 release into the medium by (PMA+Iononomycin)-stimulated Jurkatcells, in presence or absence of test compounds may be assayed by ELISA.Following the procedure described below.

Monoclonal anti-human IL-2 antibody (MAB602) (capture), biotinylatedanti-human IL-2 antibody (BAF202) (detection) and recombinant human IL-2(202-IL-010) (standard) from From R&D Systems are used.

Plate Preparation

100 μl capture antibody diluted in PBS at 5 μg/mL (PBS-Tween 0.05%) aretransferred into a 96 well ELISA plate and incubated overnight at roomtemperature.

Each well is aspirated and washed 3 times with wash buffer (PBS-Tween0.05%). After the last wash, the plate is damped.

Assay Procedure

-   1. 100 μl of sample or standard are added (2000, 1000, 500, 250,    125, 62.5, 31.25 pg/mL) and incubated 2 hours at room temperature.-   2. 3-time-wash-   3. 100 μl of biotinylated anti-human 1 μL2 at 12.5 ng/mL are added    and incubated 2 hours at room temperature.-   4. 3-time-wash-   5. 100 μl streptavidin-HRP (Zymed #43-4323) at 1:10'000 are added    and incubate 30 minutes at room temperature.-   6. 3-time-wash-   7. 100 μl substrate solution (citric acid/Na₂HPO₄ (1:1)+H₂O₂    1:2000+OPD) are added and incubated 20-30 minutes at room    temperature.-   8. 50 μl of stop solution (H₂SO₄ 20%) are added to each well.-   9. Optical density is measured using a microtiter plate reader set    to 450 nm with correction at 570 nm.

C-Jun Reporter Assay

The phosphorylation of the transcriptional factor, c-jun, by JNK in theMAP kinase signal transduction pathway can be followed via atrans-reporting system such as the commercially available PathDetect®(33).

Inhibition of phosphorylation by compounds according to formula I canthen be assessed.

A trans-reporting system allows one to follow, via Luciferase activity,the activation status of a fusion trans-activator protein. Thetrans-activator protein consists of the activation domain of thetranscriptional factor of interest (c-jun) fused with a yeasttranscriptional activator, GAL4 DNA binding domain (dbd). The GAL4 dbdhas the advantage that no known mammalian transcriptional factors canbind to it and therefore the background noise of the assay is very low.

In the present case, Hela luciferase reporter-c-Jun (HLR-c-Jun) celllines which constitutively express GAL4-cJun were used.

The MEKK-1 gene was inserted. MEKK-1 is a MAPKKK which triggers theactivation of JNK. Expression of wild type MEKK-1 is sufficient for JNKactivation (34).

Once, JNK is activated it can induce the phosphorylation of the c-jundomain of the fusion trans-activator protein (GAL4dbd-cJun) which formsa dimer. The dimer is then is able to bind to a GAL4 upstream activatingsequence (GAL4 UAS) of the reporter which activates Luciferaseexpression.

Luciferase expression is detected by luminescence using a simple assaysuch as Dual-Luciferase® Reporter Assay System (35) in which Renilla isused as a “control reporter”.

Inhibition of JNK is observed as a decrease in Luciferase expression anddetected by a decrease in luminescence.

Cell Culture

HLR-c-Jun cells are cultured in DMEM High Glc supplemented with 10% FCS(Sigma), 2 mM Glutamine (Gibco), P/S, Hygromycin b 100 μg/mL and G418250 μg/mL.

Cell Culture Preparation Cell Banks

The cells are stored frozen in cryotubes under liquid nitrogen, as 1.8mL volumes of cell suspension in culture medium containing 10% dimethylsulfoxide.

Cell Culture Thawing

When necessary, frozen vials of cells are thawed rapidly at 37° C. in awater bath by gently swirling up to semi-complete thawing. Then the cellsuspension is added to 10 mL of culture medium and then centrifuged for5 minutes at 1200 rpm. The supernatant is removed and the cell pelletreconstituted in the medium. The flasks are incubated at 37° C. in anatmosphere of 5% CO₂.

Cell Passage

The cells are serially sub-cultured (passaged) when 80% confluentmonolayers have been obtained.

The medium of each flask is removed and the monolayer is washed with10-15 mL of phosphate buffer solution (PBS).

Trypsin-EDTA solution is added to the cell monolayer, incubated at 37°C. and tapped gently at intervals to dislodge the cells. Completedetachment and disaggregation of the cell monolayer is confirmed bymicroscopy examination. The cells are then re-suspended in 10 mL ofcomplete medium and centrifuged for 5 minutes at 1200 rpm.

The supernatants are discarded, the cells are re-suspended in culturemedium and diluted 1/5 in 175 cm² flasks.

Day 0 Morning Prepare Cells for Transfections

The cells of near-confluent cultures are detached and disaggregated bytreatment with trypsin as described above.

The cells are re-suspended in culture medium and counted.

The cell suspensions are diluted with medium to give about 3.5×10⁶cells/mL and 1 mL of cell suspension are put onto 2 10 cm culture dishescontaining 9 mL of culture medium.

The plates are incubated at 37° C. in a humidified atmosphere of 5% CO₂in air.

Day 0 Evening Transfections

Control: 0.2 μg pTK Renilla, 5.8 μg pBluescript KS, 500 μl OPTIMEM(GIBCO), 18 μl Fugene 6. Induced: 0.1 μg pMEKK1, 0.2 μg pTK Renilla, 5.7μg pBluescript KS, 500 μl OPTIMEM (GIBCO), 18 μl Fugene 6 30′ RT.

The transfection mixture is added to the plated cells. The plates areincubated over night at 37° C. in a humidified atmosphere of 5% CO₂ inair.

Day 1

A 96 wells plate (100 μl of culture medium per well) is prepared.

Negative control (vehicle): 2 μl of DMSO is added to the 100 μl (intriplicate). 2 μl of compound according to formula I stock dilutions (3,1 and 0.1 mM in 100% DMSO) are added to the 100 μl (in triplicate).

The transfected cells are trypsinised and re-suspended in 12 mL ofculture medium. 100 μl of the dilution are added to each of the 96 wellsplate.

The plate is incubated over night at 37° C. in a humidified atmosphereof 5% CO₂ in air.

Day2

Test procedure: Dual-Luciferase® Reporter Assay System (35).

The medium is removed from the plate and the cells are washed two timeswith 100 μl PBS. Lysis reagent is applied (Passive Lysis Buffer, PLB).Into each culture well 5 μl of 1×PLB are dispensed. The culture platesare placed on a rocking platform or orbital shaker with gentlerocking/shaking to ensure complete coverage of the cell monolayer with1×PLB. The culture plates are rocked at room temperature for 15 minutes.20 μl of the lysate are transferred into a white opaque 96 well plate.The luminometer reading is recorded.

-   -   50 μl of Luciferase Assay Reagent 11 are injected and readings        are recorded at 5 and 10 minutes.        50 μl of Stop & Glo® Reagent are injected and readings are        recorded at 5 and 10 minutes.

The relative luminescence is then measured: RLU Luciferase/RLU Renilla.

LPS Induced Endotoxin Shock in Mice

Endotoxins are the lipopolysaccharides (LPS) constituents of the outermembrane of Gram negative bacteria. Response to LPS has been shown toinvolve the activation of different cell populations and to lead to theexpression of various inflammatory cytokines that include tumor necrosisfactor-alpha (TNFα) and interferon gamma (IFN-γ).

As LPS is known to stimulate the activation of various MAP kinasepathways, including JNK (36), the ability of JNK inhibitors can betested after the JNK signaling pathway has been switched on by a LPSchallenge.

The activity as JNK inhibitors of compounds of formula may be assessedafter a LPS challenge using the following protocol:

LPS (S. abortus-Galanos Lab.-) is injected (200 μg/kg, i.v.) to MaleC57BU6 mice to induce endotoxin shock. Compounds according to formula I(0.1, 1, 10 mg/kg) or NaCl (200 uM) are injected intravenously (10mL/kg) 15 min before the LPS challenge. Heparinized blood was obtainedfrom the orbital sinus at different time points after the LPS challenge,and the blood was centrifuged at 9'000 rpm for 10 min at 4° C. tocollect supernatant. Measurement of cytokines production such as TNFαand IFNγ by mouse is performed with an ELISA kit such as Duoset® DY410for TNFα: and DY 485 for IFN γ. Other ELISA assays such as described in(37) can be used.

Global Ischemia in Gerbils

The gerbil bilateral carotid occlusion is a well-described animal modelof acute ischemic stroke and involves relatively easy surgicaltechniques.

The neuronal degeneration in the hippocampus develops over several daysand is often referred as “delayed neuronal death”. In addition, theneurodegeneration observed histologically is obvious and easilyquantified (37). Furthermore, the histopathology seen in the gerbil issimilar to that observed in the hippocampal CA1 region of the humanbrain following a cardiac arrest. Behavior observations, such as memorytests, could even be performed in the case of gerbils. This kind oftests for appreciation of the degree of recovery is not easilymanageable in other models such as in rat whose learning abilities aremuch poorer (39).

The neuroprotective effect according to formula I to protect may beassessed using the gerbil global ischemia model and such a protocol:

—1—Method *Surgery

-   -   Anesthesia with isoflurane (0.5-4%).    -   The common carotid arteries (left and right) are freed from        tissue.    -   Occlusion of the arteries using Bulldog microclamps during 5        min.    -   Removal of clamps (reperfusion)    -   Stabulation of the animals under heating lamp until awake.    -   Stabulation of the animals in the animal in individual cages.

*Sacrifice of the Animals

-   -   7 days after ischemia (Decapitation or overdose of        pentobarbital).    -   Sampling of the brain.

*Histological Parameters

-   -   Freezing of the brain in isopentane (−20° C.)    -   Slicing of the hippocampus using a cryo-microtome (20 μm).    -   Staining with cresyl violet method    -   Evaluation of the lesions (in CA1/CA2 subfields of the        hippocampus) by a modified Gerhard & Boast score (40).

—2—Treatment

-   -   Administration of the compound according to formula I or the        vehicle: 15 min, 24 hours and 48 hours after reperfusion (5-10        min after the recovery of the anesthesia).    -   Standard protocol        50 animals: 5 groups of 8-(group A: control, groups B-D: test        article at 3 doses and group E: reference compound (Orotic acid        3×300 mg/kg, ip).

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1. A sulfonamide according to formula I

a geometrical isomer thereof, an optically active form thereof, anenantiomer thereof, a diastereomer thereof, a mixture thereof, or a saltthereof wherein: Ar¹ is a substituted or unsubstituted aryl group; X isO or S; Ar² is a substituted or unsubstituted thienylene group; R¹ andR² are independently selected from the group consisting of hydrogen anda C₁-C₆-alkyl group; R^(a), R^(a′), R^(b), R^(b′) are independentlyselected from the group consisting of hydrogen and C₁-C₆-alkyl; orR^(a′) and R^(a) or R^(b′) together with the carbon atoms they arelinked, form a substituted or unsubstituted 5-8-membered saturated,partially unsaturated or aromatic ring containing optionally one or moreheteroatoms selected from O, N, S; R³ is selected from the groupconsisting of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl,heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S; arylC₁-C₁₀-alkyl and heteroaryl C₁-C₁₀-alkyl; or R³ and R^(a) or R^(a′)form, together with the N atom linked to R³, a 5-8-membered saturatedring, containing optionally at least one further heteroatom selectedfrom O, N, S; R⁴ is selected from the group consisting of H and—C(H)R⁵R⁶; R⁵ and R⁶ are independently selected from the groupconsisting of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl,heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S; arylC₁-C₁₀-alkyl and heteroarylC₁-C₁₀-alkyl; m is an integer from 1 to 5; nis an integer from 0 to 2; and p is an integer from 1 to 10; wherein thecompound according to formula I is not:N-[[5-[[[3-[[4-[(3-aminopropyl)amino]butyl]aminopropyl]amino]sulfonyl]-2-thienyl]methyl]-Benzamide,N-[[5-[[[3-[[4-[(3-aminopropyl)amino]butyl]amino]propyl]amino]sulfonyl]-2-thienyl]methyl]-4-chloro-Benzamide,orN,N′-[1,4-butanediylbis(imino-3,1-propanediyliminosulfonyl-5,2-thiophenediylmethylene)]bis[4-chloro-]Benzamide.2. The sulfonamide according to claim 1, wherein Ar¹ is phenyl,optionally substituted by a group selected from C₁-C₆-alkyl,C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, amino, acylamino,aminocarbonyl, C₁-C₆-alkoxycarbonyl, aryl, carboxyl, cyano, halogen,hydroxy, nitro, sulfonyl and C₁-C₆-thioalkoxy.
 3. The sulfonamideaccording to claim 1, wherein Ar¹ is an unsubstituted or substitutedphenyl.
 4. The sulfonamide according to claim 1, wherein Ar² isthienylene optionally substituted by a group selected from C₁-C₆-alkyl,C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, amino, acylamino,aminocarbonyl, C₁-C₆-alkoxycarbonyl, aryl, carboxyl, cyano, halogen,hydroxy, nitro, sulfonyl and C₁-C₆-thioalkoxy.
 5. The sulfonamideaccording to claim 1, wherein Ar² is an unsubstituted or substitutedthienylene group.
 6. The sulfonamide according to claim 1, wherein Ar¹is selected from the group consisting of halogenophenyl, nitrophenyl,hydroxyphenyl, alkoxy phenyl, and 3,4,-dihydroxyphenyl, X is O, R¹ ishydrogen, m is 1 and Ar is thienylene.
 7. The sulfonamide according toclaim 1, wherein: Ar¹ is 4-chlorophenyl; X is O; R¹ and R² are bothhydrogen; m is 1; n is 0, 1 or 2; Ar² is a thienylene or phenylenegroup; R^(a), R^(a′), R^(b), R^(b′) are hydrogen; R³ is hydrogen,C₁-C₆-alkyl or aryl; R⁴ is selected from the group consisting of H,C₁-C₁₀-alkyl, aryl C₁-C₁₀-alkyl, CH₂—(C₃-C₈-cycloalkyl),CH₂—(C₃-C₈-heterocycloalkyl), CH₂-aryl and a CH₂-heteroaryl group. 8.The sulfonamide according to claim 1, wherein Ar¹ is a 4-chlorophenyl, Xis O, R¹ and R² are hydrogen, m is 1; n is 0, 1 or 2; Ar² is athienylene or phenylene group, R^(a) or R^(a′) forms a 5-6 membered ringwith R³; R³ is hydrogen, C₁-C₆-alkyl or aryl; R⁴ is selected from thegroup consisting of H, C₁-C₁₀-alkyl, aryl C₁-C₁₀-alkyl,CH₂—C₃-C₈-cycloalkyl, CH₂—C₃-C₈-heterocycloalkyl, aryl and aCH₂-heteroaryl group.
 9. The sulfonamide according to claim 1, whereinAr¹ is a 4-chlorophenyl; X is O; R¹ and R² are hydrogen; m is 1; n is 0,1 or 2; Ar² is a thienylene or phenylene group; R^(a) forms a 5-6membered ring with R^(a′); R³ is hydrogen, C₁-C₆-alkyl or aryl; R⁴ isselected from the group consisting of H, C₁-C₁₀-alkyl, arylC₁-C₁₀-alkyl, CH₂—C₃-C₈-cycloalkyl, CH₂—C₃-C₈-heterocycloalkyl, aryl andCH₂-heteroaryl group.
 10. A medicament comprising the sulfonamideaccording to claim 1 and one or more pharmaceutically acceptablediluents or excipients.
 11. A method for treating at least one disorderin a person in need thereof comprising administering the sulfonamideaccording to formula I

wherein: Ar¹ is a substituted or unsubstituted aryl group; X is O or S;Ar² is a substituted or unsubstituted thienylene group; R¹ and R² areindependently selected from the group consisting of hydrogen and aC₁-C₆-alkyl group; R^(a), R^(a′), R^(b), R^(b′) are independentlyselected from the group consisting of hydrogen and C₁-C₆-alkyl; orR^(a′) and R^(a) or R^(b′) together with the carbon atoms they arelinked, form a substituted or unsubstituted 5-8-membered saturated,partially unsaturated or aromatic ring containing optionally one or moreheteroatoms selected from O, N, S; R³ is selected from the groupconsisting of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl,heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S; arylC₁-C₁₀-alkyl and heteroaryl C₁-C₁₀-alkyl; or R³ and R^(a) or R^(a′)form, together with the N atom linked to R³, a 5-8-membered saturatedring, containing optionally at least one further heteroatom selectedfrom O, N, S; R⁴ is selected from the group consisting of H and—C(H)R⁵R⁶; R⁵ and R⁶ are independently selected from the groupconsisting of H, C₁-C₁₀, alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl,heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S, arylC₁-C₁₀-alkyl and heteroaryl C₁-C₁₀-alkyl; m is an integer from 1 to 5; nis an integer from 0 to 2; and p is an integer from 1 to 10; an isomerthereof, an optionally active form thereof, a diastereomer thereof, anda mixture thereof; to the person in an amount sufficient to treat the atleast one disorder, wherein the at least one disorder is selected fromthe group consisting of epilepsy, Huntington's disease, Parkinson'sdisease, retinal disease, spinal cord injury, Multiple Sclerosis, headtrauma and ischemia; a cardiovascular disease; stroke; arterosclerosis;myocordial infarction; myocordial reperfusion injury; an ischemiccondition; heart injury; renal injury; kidney injury; brain reperfusioninjury and renal failure.
 12. A method for treating at least onedisorder in a mammal in need thereof, comprising administering thesulfonamide according to claim 1 to the mammal in need thereof in anamount sufficient to treat the at least one disorder, wherein the atleast one disorder is selected from the group consisting of Alzheimer'sdisease, an auto-immune disease, inflammatory bowel disease (IBD),rheumatoid arthritis, asthma, septic shock, transplant rejection,cancer, breast-cancer, colorectal-cancer, pancreatic cancer, ovariancancer, prostate cancer, testicular cancer, hepatic cancer, kidneycancer, and lung cancer.
 13. A pharmaceutical composition comprising atleast one sulfonamide according to claim 1 and one or more of apharmaceutically acceptable carrier, diluent or excipient.
 14. A processfor the preparation of the sulfonamide according to claim 1 wherein R⁴is not H, comprising reductively aminating a carbonyl group of formulaVII with a compound of formula VI


15. A process for the preparation of the sulfonamide according to claim1, wherein R⁴ is H, comprising deprotecting a compound of formula IV


16. The process according to claim 14, wherein the compound of formulaVI is obtained by deprotecting a compound of formula IV


17. The process according to claim 15, wherein the compound of formulaIV is obtained by reacting a compound of formula II with a compound offormula III


18. A process for the preparation of the sulfonamide according to claim1, comprising N-sulfonylating a compound of formula X with asulfonylchloride of formula III


19. The process according to claim 18, wherein the compound of formula Xis obtained by deprotecting a compound of formula IX

wherein P is a protecting group.
 20. The process according to claim 19,wherein the compound of formula IX is obtained by reductively aminatinga compound of formula VII with a compound of formula VIII

wherein P is a protecting group.
 21. A process for the preparation ofthe sulfonamide according to claim 1, comprising reductively aminating acarbonyl group of formula XIII with an amine of formula XIV


22. The process according to claim 21, wherein the compound of formulaXIII is obtained by oxidizing a compound of formula XII


23. The process according to claim 22, wherein the compound of formulaXII is obtained by sulfonylating a compound of formula XI


24. A method for modulating a JNK pathway in a mammal comprisingadministering the sulfonamide according to claim 1 to the mammal in anamount effective for modulating the JNK pathway.
 25. The method asclaimed in claim 24, wherein the sulfonamide is administered in anamount effective for the prevention of one or more disorders associatedwith the abnormal expression or activity of JNK.
 26. The method asclaimed in claim 25, wherein the sulfonamide is administered for thetreatment or prevention of one or more disorders associated with theabnormal expression or activity of at least one of JNK2 or JNK3.
 27. Themethod as claimed in claim 11, wherein X is O.